Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial

Ventura-López, Claudia; Cervantes-Luévano, Karla; Aguirre-Sánchez, Janet S.; Flores-Caballero, Juan C.; Álvarez-Delgado, Carolina; Bernáldez-Sarabia, Johanna; Sánchez-Campos, Noemí; Lugo-Sánchez, Laura A.; Rodríguez-Vázquez, Ileana C.; Sander-Padilla, Jose G.; Romero-Antonio, Yulia; Arguedas-Núñez, María M.; González-Canudas, Jorge; Licea-Navarro, Alexei F.

doi:10.1016/j.biopha.2022.113223

Cited by 31 publications

(22 citation statements)

References 35 publications

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“…22,23 Experimentally, metformin has in-vitro activity at a physiologically relevant dose against SARS-CoV-2 in cell culture and in human lung tissue, ex vivo, and in a phase 2 clinical trial. [24][25][26][27] In addition to in vitro and in vivo activity against SARS-CoV-2, metformin has been extensively studied for its anti-inflammatory actions. In human bronchial and lung epithelial cell lines infected with SARS-CoV-2, metformin restored autophagic flux, inhibited cleavage of caspase-1 by non-structural protein 6 (NSP6), and inhibited maturation and release of interleukin-1𝛽 and interleukin-18.…”

Section: Discussionmentioning

confidence: 99%

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Bramante

Buse

Liebovitz

et al. 2022

Preprint

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Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial. Trial registration:NCT04510194; IND 152439

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Section: Discussionmentioning

confidence: 99%

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Bramante

Buse

Liebovitz

et al. 2022

Preprint

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“…For example, it was shown very early that the infection of the human respiratory system with the SARS coronavirus can only be reproduced in realistically constructed in vitro models, with a pseudostratified epithelium with polarized cells [ 12 ]. The requirements for basic and applied research in the course of the SARS-CoV-2 pandemic have shown the limitations of the existing in vitro airway models and contributed to their further development [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Optimization of Primary Human Bronchial Epithelial 3D Cell Culture with Donor-Matched Fibroblasts and Comparison of Two Different Culture Media

Maurer

Walles

Wiese-Rischke

2023

IJMS

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In vitro airway models are increasingly important for pathomechanistic analyses of respiratory diseases. Existing models are limited in their validity by their incomplete cellular complexity. We therefore aimed to generate a more complex and meaningful three-dimensional (3D) airway model. Primary human bronchial epithelial cells (hbEC) were propagated in airway epithelial cell growth (AECG) or PneumaCult ExPlus medium. Generating 3D models, hbEC were airlifted and cultured on a collagen matrix with donor-matched bronchial fibroblasts for 21 days comparing two media (AECG or PneumaCult ALI (PC ALI)). 3D models were characterized by histology and immunofluorescence staining. The epithelial barrier function was quantified by transepithelial electrical resistance (TEER) measurements. The presence and function of ciliated epithelium were determined by Western blot and microscopy with high-speed camera. In 2D cultures, an increased number of cytokeratin 14-positive hbEC was present with AECG medium. In 3D models, AECG medium accounted for high proliferation, resulting in hypertrophic epithelium and fluctuating TEER values. Models cultured with PC ALI medium developed a functional ciliated epithelium with a stable epithelial barrier. Here, we established a 3D model with high in vivo–in vitro correlation, which has the potential to close the translational gap for investigations of the human respiratory epithelium in pharmacological, infectiological, and inflammatory research.

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“…More recently, several randomised trials on the treatment of COVID-19 have used viral load as the primary outcome, demonstrating that ivermectin (7) reduced SARS-CoV-2 viral load in comparison with convalescent plasma (8). Metformin glycinate has been reported to reduce SARS-CoV-2 viral load in a double-blind Phase IIb clinical trial (9). In a very preliminary paper, we reported that 26 patients with COVID-19 treated with HCQ with or without azithromycin had a significant shorter virus shedding period compared to 16 untreated patients with COVID-19 (10).…”

Section: Introductionmentioning

confidence: 99%

Viral clearance in patients with COVID-19: associated factors and the role of antiviral treatment

Brouqui

Lagier

Parola

et al. 2023

Preprint

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The role of hydroxychloroquine (HCQ) in lowering the viral load of patients with COVID-19 is controversial. In our Institute, we treated more than 30,000 people with COVID-19 in 2020 and 2021, using the same diagnostic tools and the same treatment dosages. In this retrospective comparative study of data collected over this period, we aimed to compare the viral clearance in the nasopharynx as determined by qPCR in patients who were treated with HCQ and those who were not. As a new feature, we adjusted the data according to the most significant confounding factors (age, initial viral load, and timescale between the onset of symptoms and treatment). Of the 1 276 patients selected from our database, 776 were treated with HCQ and 500 were not. Viral clearance in the treatment group was reached significantly earlier than in the non-treatment group, at days 5, 10 and 30. These differences remain significant after adjustments for confounding factors. In conclusion, although age, initial viral load, and time to treatment do influence the viral load in patients with COVID-19, hydroxychloroquine associated with azithromycin still independently significantly lowered viral load more rapidly than other treatments, including azithromycin alone.

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Treatment with metformin glycinate reduces SARS-CoV-2 viral load: An in vitro model and randomized, double-blind, Phase IIb clinical trial

Cited by 31 publications

References 35 publications

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Optimization of Primary Human Bronchial Epithelial 3D Cell Culture with Donor-Matched Fibroblasts and Comparison of Two Different Culture Media

Viral clearance in patients with COVID-19: associated factors and the role of antiviral treatment

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